Process for producing 5-hydroxytryptamine



United States Patent PROCESS FOR PRODUCING S-HYDROXY- TRYPTAMINE KennethE. Hamlin, Lake Blulf, Ill., assignor to Abbott Laboratories, NorthChicago, Ill., a corporation of Illinois No Drawing. Application October9, 1951, Serial No. 250,573

11 Claims. (CL. 260319) This invention relates to a chemical process andmore particularly to a process for preparing S-hydroxytryptaminehydrochloride and the novel intermediates thereof.

In general the process is a four step synthesis starting fromS-benzyloxyindole. The reactions are schematically shown by thefollowing formulae:

(III) R0 CHzCHzNHaBCL no CHzCHzNHzHC L I l-Z Example I A mixture of 3gm. of S-benzyloxyindole (I), 1.8 gm. of formalin, and 1.14 gm. ofdimethylamine dissolved in 5 cc. of glacial acetic acid is allowed tostand at room temperature for 3 hours. During the last part of the timeperiod, the solution is made slightly alkaline with dilute sodiumhydroxide solution precipitating a yellow oil. After standing, the oilbecomes crystalline, and the crystals are filtered from the mixture. Onrecrystallization from ethyl acetate, the S-benzylox'ygramine (II) meltsat 137138 C.

Example II About 8 gm. of 5-benzyloxygramine are admixed with a solutionof about 8 gm. of sodium cyanide in 11 cc. of water and cc. of ethanol.The mixture is refluxed for about 8 hours, and after cooling therefluxed mixture, 30 cc. of water is added. The alcohol is removed undervacuum leaving a residual brown oil, which crystallizes on cooling. Thecrystalline material is Washed, dried and recrystallized from methanol.The crystalline 5-benzyloxyindole-3-acetamide (III) melts at 158 CExample III An ether solution of about 2 gm. of lithium aluminum hydrideand 1 gm. of 5-benzyloxyindole-3-acetamide is refluxed for about 8hours, and sufficient water is then added to decompose the complex(about equal parts of water). The ether solution is filtered and driedover magnesium sulfate. S-benzyloxytryptamine hydrochloride (IV) isformed by treating the ether solution of the base with ethereal hydrogenchloride. The crystalline salt after recrystallizing from anethanol-ether solution, melts at 265 C.

Example IV A solution of about 1 gm. of S-benzyloxytryptaminehydrochloride in methanol is catalytically hydrogenated using aplatinum-charcoal catalyst. An equivalent of hydrogen is absorbed inapproximately three minutes. The mixture is then filtered and themethanol is removed under vacuum. The highly colored residue is treatedwith anhydrous ether giving a grey-brown solid precipitate. Aftertreatment with charcoal and further recrystallization, a whitecrystalline hygroscopic material is obtained. After thorough drying, theS-hydroxytryptamine hydrochloride (V) melts at l67l68 C.

The conversion of 5-benzyloxygramine to S-benzyloxyindole-3-acetamide isproduced by the reaction with a cyanide salt. Salts such as the alkaliand alkali metal cyanides may be utilized in the reaction. Further, thecatalyst in the hydrogenation of S-benzyloxytryptamine to produce theS-hydroxy compound may be a noble metal or a noble metal oxide common inthe art of catalytic hydrogenation.

Others may readily adapt the invention for use under various conditionsof service, by employing one or more of the novel features disclosed orequivalents thereof. As at present advised with respect to the apparentscope of my invention, I desire to claim the following subject matter.

I claim: 1. The process which comprises intimately admixing-5-benzyloxyindole with formalin and dimethylamine,

heating the resulting S-benzyloxygramine with a cyanide salt, reducingthe resulting S-benzyloxyindole-3-acetamide, hydrogenating the resultingS-benzyloxytryptamine to produce 5-hydroxytryptamine.

2. The process which comprises admixing 5-benzyloxyindole with formalinand dimethylamine in the presence of acetic acid, refluxing theresulting S-benzyloxygramine with sodium cyanide in an ethanol-watermixture, refluxing the resulting 5-benzyloxyindole-3-acetamide withlithium aluminum hydride in an ether solution, hydrogenating theresulting S-benzyloxytryptamine in the presence of a platinum-charcoalcatalyst to produce S-hydroxytryptamine.

3. The process which comprises admixing S-benzyloxyindole with formalinand dimethylamine in the presence of acetic acid, refluxing theresulting S-benzyloxygramine with a cyanide salt in aqueous solution,refluxing the resulting 5-benzyloxyindole-3-acetamide with lithium Ialuminum hydride, reacting the resulting S-benzyloxytryptamine withhydrogen chloride to produce 5-benzyloxytryptamine hydrochloride, andhydrogenating the 5- benzyloxytryptamine hydrochloride to produceS-hydroxytryptarnine hydrochloride.

4. The process which comprises admixing S-henzyloxyindole with formalinand dimethylamine in the presence of acetic acid, refluxing theresulting S-berizyloxygramine with a cyanide salt in aqueous solution,refluxing the resulting 5-benzyloxyindole-3-acetamide with lithiumaluminum hydride, and reacting the resulting S-benzyloxytryptamine withhydrogen chloride to produce S-bcnzyloxytryptamine hydrochloride. 5. Theprocess which comprises intimately admixing S-benzyloxyindole withformalin and dimethylamine in the presence of glacial acetic acid toform S-benzyloxygramine.

6. The process which comprises refluxing S-benzyloxygrarnine with sodiumcyanide in a water-ethanol mixture to produce5-benzyloxyindole-3-acetamide.

7. The process which comprises refluxing S-benzyloxyindole-3-acetamidewith lithium aluminum hydride in ethereal solution to formS-benzyloxytryptarnine.

8. The process which comprises intimately admixing S-benzyloxyindolewith formalin and dimethylamine to form 5 benzyloxygramine, heating saidS-benzyloxy- 5 hydrochloride, and hydrogenating the last named productto form S-hydroxytryptamine hydrochloride.

9. In the process of producing S-hydroxytryptamine, the steps whichcomprise heating 5-benzyloxyindole-3- acetamide with lithium aluminumhydride, admixing the ,0 resulting S-benzyloxytryptamine with hydrogenchloride,

and hydrogenating the resulting S-bcnzyloxytryptamine hydrochloride toform.5-hydroxytryptamine hydrochloride.

10. The compound S-benzyloxygramine.

,;, ll. The compound 5-benzyloxyindole-3-acetarnide.

References Cited in the file of this patent UNITED STATES PATENTSJenkins Feb. 18, 1947 OTHER REFERENCES Wieland et al., Annalen derChemie, vol. 513 (1934), pp. 1-25.

25 Kornfeld, Jr., Org. Chem., vol. 16, pp. 806-809 (May

1. THE PROCESS WHICH COMPRISES INTIMATELY ADMIXING 5-BENZYLOXYINDOLEWITH FORMALIN AND DIMETHYLAMINE, HEATING THE RESULTING5-BENZYLOXYGRAMINE WITH A CYANIDE SALT, REDUCING THE RESULTING5-BENZLOXYINDOLE-3-ACETAMIDE, HYDROGENATING THE RESULTING5-BENZYLOXYTRYPTAMINE TO PRODUCE 5-HYDROXYTRYPTAMINE.